1. Field of the Invention
The present invention relates to a process for preparing cephalosporin antibiotics, including cefprozil, cefatrizine, and cefadroxil, using a 4-hydroxyphenylglycine derivative.
2. Description of the Related Art
Oral cephalosporin antibiotics, including cefprozil, cefatrizine, and cefadroxil, commonly have a 4-hydroxyphenylglycine group, as represented by the following formula:

The compound of the above formula is cefprozil when A is —C═CH—CH3, cefatrizine when A is 1H-1,2,3-triazole-4-yl-thiomethyl, and cefadroxil when A is —CH3.
Conventionally, there have been known various processes for preparing oral cephalosporin antibiotics, such as cefprozil, cefatrizine, and cefadroxil, by reacting reactive derivatives of 4-hydroxyphenylglycine with 3-cephem compounds.
For example, U.S. Pat. No. 3,985,741 discloses a process for preparing a cefadroxil, which includes reacting 4-hydroxyphenylglycine and ethylchloroformate in N-methylmorpholine to obtain an anhydride, followed by reaction with 7-amino-deacetoxy-cephalosporanic acid (7-ADCA). However, the yield and quality of the product are poor.
U.S. Pat. Nos. 4,520,022, 4,591,641, and 4,661,590 disclose a condensation reaction between 4-hydroxyphenylglycine with a protected amino group and a cephem compound in the presence of N,N′-dicyclohexylcarbodimide. However, N,N′-dicyclohexylurea produced after the condensation reaction is not easily removed, which restricts industrial applications.
U.S. Pat. No. 4,336,376 discloses a process for preparing a cefadroxil, which includes reacting a 4-hydroxyphenylglycine salt having a protected amino group with trimethylsilyl-2-oxazolidinone to protect a 4-hydroxyl group followed by reaction with acylchloride to obtain a 4-hydroxyphenylglycine anhydride and then reaction with 7-ADCA. However, silylation is prerequisite and these reactions are annoying, and thus, this process is not suitable for industrial application.
U.S. Pat. No. 4,708,825 discloses a technique of reacting 4-hydroxyphenylglycine having a substituted amino group with thionyl chloride using a gaseous hydrogen chloride to obtain a 4-hydroxyphenylglycyl chloride hydrochloride followed by reaction with a cephem compound. However, handling property of the thionyl chloride and the gaseous hydrogen chloride is poor, and thus, this technique is not suitable for industrial application.
U.S. Pat. Nos. 3,925,418, 4,243,819, and 4,464,307 disclose a process for producing 4-hydroxyphenylglycine using excess phosgene. However, difficulty in handling of highly toxic phosgene, removal of excess residual phosgene, and control of reaction conditions renders mass production difficult.
As a process for preparing a reactive anhydride of 4-hydroxyphenylglycine, there are reported a method for the preparation of acid chloride using phosphorus pentachloride, phosphorus oxychloride, or thionyl chloride, and a method for the preparation of active ester using imidazole, mercaptobenzothiazole, or hydroxybenzotriazole. However, an acid chloride of 4-hydroxyphenylglycine has poor reactivity due to a hydroxyl group and an active ester of 4-hydroxyphenylglycine has poor reactivity and involves a side reaction.
In addition, Korean Patent Laid-Open Publication Nos. 2002-69431, 2002-69432, 2002-69437, and 2002-69440 disclose a process for preparing a pivaloyl or succinimide derivative of 4-hydroxyphenylglycine and a process for preparing a cephem compound such as cefprozil using the pivaloyl or succinimide derivative of 4-hydroxyphenylglycine.
Meanwhile, there have been known various preparation processes for 3-(Z)-propenyl cephem derivative which is a compound useful as an intermediate for preparation of cefprozil which is an oral cephalosporin antibiotic.
WO93/16084 discloses a process of selectively separating a 3-(Z)-propenyl cephem compound by means of a hydrochloride, metal, or tertiary amine salt of 7-amino-3-(1-propen-1-yl)-3-cephem-carboxylic acid or by adsorption chromatography. However, there is a disadvantage in that separation and purification are cost-ineffective.
U.K. Patent No. 2,135,305 discloses a process for preparing cefprozil from a 4-hydroxyphenylglycine compound with a t-butoxycarbonyl-protected amino group and a cephem compound with a benzhydryl-protected carboxyl group. However, incorporation of a 3-propenyl group after acylation lowers reaction efficiency and high-performance liquid chromatography is required for isomer separation, which render industrial application difficult.
U.S. Pat. No. 4,727,070 discloses a technique of removing an E-isomer cefprozil from a mixture of Z/E cefprozil, which includes incorporating an active group such as sodium imidazolidinone into the mixture of Z/E cefprozil by reaction of the mixture of Z/E cefprozil with acetone followed by deprotection. However, purification by chromatography incurs enormous costs.
In view of the above problems, Korean Patent Laid-Open Publication No. 2002-80838 discloses a process for preparing a 3-(Z)-propenyl cephem compound by reacting a phosphoranylidene cephem compound with acetaldehyde in a mixed solvent essentially consisting of ether in the presence of a base. According to a disclosure in this patent document, ether is essentially used. In this respect, in the case of using methylenechloride or tetrahydrofuran, even when other reaction conditions, for example, reaction temperature, reaction duration, base, catalyst, and the like are adjusted, it is very difficult to adjust the content of the Z-isomer to more than 83%.